Background: Water buffaloes are important milch species of tropical and subtropical countries. In general, they are considered to more resistant to diseases compared to crossbred cattle. However, a recent problem of tick-borne diseases in the water buffaloes by the field veterinarians and farmers causing production losses was observed. The study was conducted to explore the spectrum of tick-borne diseases (TBDs) infections in buffaloes and analyze the associated risk factors. Methods: Acute-phase response, cytokine and oxidative stress in infected buffaloes with TBDs were evaluated and compared with the negative buffaloes (control) to elucidate their role in pathogenesis and outcome of infection. The study was undertaken in 107 tick-infested water buffaloes. The conventional Giemsa stained blood smear (GSBS) based confirmation and classification of infection of haemo-parasites were made. The statistical model was used to understand their relevance with TBDs. Conclusion: Tick-borne disease in water buffaloes must be looked upon seriously to maintain good productivity. The buffaloes are often accompanied by low and un-yielding clinical symptoms due to associated co-infections of haemo-parasites. Our study showed that the buffaloes had a high prevalence (47.66%) of haemo-parasites transmitted by the ticks associated with co-infections and a low level of parasitemia. Most buffaloes responded symptomatically with the different modalities administered. Production parameter was not restored post 15 days of treatment. Oxidative stress is one of the important mechanisms of production losses in infected buffaloes.